The present invention relates to compounds and compositions comprising cannabinoid receptor modulators, to processes for preparing such compounds and compositions, and to the use of cannabinoid receptor modulators in treating respiratory and non-respiratory diseases.
Delta-9 THC, the principle active component of marijuana, is a member of a large family of lipophilic compounds (i.e., cannabinoids) that mediate physiological and psychotropic effects including immunosuppression, analgesia, inflammation, emesis, and intraocular pressure. Cannabinoids work through selective binding to G-protein coupled cannabinoid receptors. Two types of cannabinoid receptors have been cloned including CB1 (L. A. Matsuda et al. Nature, Vol. 346 [1990], pp. 561-564), and CB2 (S. Munro et al, Nature, Vol. 365 [1993], pp. 61-65). The CB1 receptor is found mainly on cells of the central nervous system, while the CB2 receptor is found mainly on cells of the peripheral nervous system including cells comprising the immune system such as lymphoid cells.
Compounds that reportedly bind to the cannabinoid G-protein receptors are disclosed in European Patent Documents Nos. EP 0570920 and EP 0444451; International Publications Nos. WO 97/29079, WO 99/02499, WO 98/41519, and WO 9412466; U.S. Pat. Nos. 4,371,720, 5,081,122, 5,292,736, and 5,013,387; and French Patent No. FR 2735774, each of which is incorporated herein by reference.
Applicants have discovered that cannabinoid receptor modulators including cannabinoid receptor agonists are useful in treating respiratory disease, such as chronic pulmonary obstructive disorder, emphysema, asthma, and bronchitis. In one aspect of the invention, there is provided the use of cannabinoid receptor modulators in treating respiratory disease in a mammal comprising administering to said mammal an effective amount of at least one cannabinoid receptor modulator. Advantageously, the cannabinoid receptor modulator for this aspect of the invention is a CB2-receptor modulator.
The present invention is also directed to compounds and pharmaceutical compositions comprising at least one cannabinoid receptor modulator, and to the use of at least one such compound in treating respiratory and non-respiratory leukocyte activation-associated disorders, wherein the compound has the formula (I): 
or a pharmaceutically-acceptable salt or hydrate thereof, in which:
A and B are selected from carbon and nitrogen so that ring X defines a pyrrole, pyrazole, or imidazole ring; wherein when A is nitrogen, the group xe2x80x94C(xe2x95x90O)NR1R2 is attached to atom C-3 and R5 does not exist; and when A is carbon, one of the group xe2x80x94C(xe2x95x90O)NR1R2 and R5 is attached to A and the other of xe2x80x94C(xe2x95x90O)NR1R2 and R5 is attached to atom C-3; and when B is carbon, two R4 groups attached to B and atom C-5, respectively, optionally form a fused 6-membered aryl or 6-membered heteroaryl having one heteroatom which is nitrogen, wherein said aryl or heteroaryl has three or four groups R6;
f is 0 or 1;
g is 1 or 2;
R1 and R2 are independently selected from hydrogen, alkyl, substituted alkyl, heterocycloalkyl, cycloalkyl, aryl, and heterocyclo; or R2 together with R1 or R5 forms a five or six membered heterocyclo;
R3 is hydrogen, alkyl, substituted alkyl, heterocycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heterocyclo, or alkoxy, or forms a heterocyclo with one of R6;
R4 is attached to atom C-5 and optionally B and at each occurrence independent of each other R4 is selected from hydrogen, alkyl, substituted alkyl, heterocycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heterocyclo, hydroxy, alkoxy, amino, aminoalkyl, cyano, halogen, alkylamide, NR8C(xe2x95x90O)R9, and S(O)uR10; or when B is carbon, optionally two R4 groups taken together form a six-membered aryl or heteroaryl having three or four R6;
R5 is attached to A or atom C-3 and is hydrogen, alkyl, substituted alkyl, heterocycloalkyl, alkenyl, substituted alkenyl, alkoxy, aryl, or heterocyclo; or R5 together with R2 forms a heterocyclo;
R6 at each occurrence independent of each other R6 is selected from hydrogen, alkyl, substituted alkyl, heterocycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted aryl, heterocyclo, hydroxy, alkoxy, amino, aminoalkyl, cyano, halogen, alkylamide, nitro, NR8C(xe2x95x90O)R9, S(O)uR10, xe2x80x94C(xe2x95x90O)R8, xe2x80x94CO2R8, xe2x80x94S(O)2NR8R10, xe2x80x94C(xe2x95x90O)N(R8)O(R9), xe2x80x94C(xe2x95x90O)NR8R9, and xe2x80x94OC(xe2x95x90O)R10; and/or one R6 group together with R3 forms a heterocyclo;
R8 and R9 at each occurrence independent of each other R8 and R9 are selected from hydrogen, alkyl, substituted alkyl, heterocycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, and heterocyclo; or R8 and R9 together form a three-to-eight membered heterocyclo; or R8 together with R10 forms a three-to-eight membered heterocyclo; and
R10 at each occurrence independent of each other R10 is selected from alkyl, substituted alkyl, heterocycloalkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl, or forms a heterocyclo with R8; and u is 0, 1, 2 or 3.
According to another aspect of the invention, there are provided pharmaceutical compositions useful for treating respiratory disease comprising an effective amount of at least one cannabinoid receptor modulator according to formula (I) in a pharmaceutically-acceptable carrier or modulator. In a further aspect of the invention, there are provided compounds useful as cannabinoid receptor modulators and pharmaceutical compositions comprising such cannabinoid receptor modulators, wherein the compounds comprise selected compounds according to formula (I), as defined hereinafter. In a still further aspect of the invention, there is provided a process of preparing one or more intermediates to compounds of formula (I), and processes for preparing compounds of formula (I).
The following are definitions of terms used in this specification. The initial definition provided for a group or term herein applies to that group or term throughout the present specification, individually or as part of another group, unless otherwise indicated.
The term xe2x80x9calkylxe2x80x9d refers to straight or branched chain hydrocarbon groups having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms. The expression xe2x80x9clower alkylxe2x80x9d refers to alkyl groups of 1 to 4 carbon atoms.
The term xe2x80x9csubstituted alkylxe2x80x9d refers to an alkyl group as defined above having one, two or three substituents selected from the group consisting of halo, cyano, nitro, amino, aminoalkyl, hydroxy, ORa, xe2x80x94SH, keto (xe2x95x90O), xe2x80x94C(xe2x95x90O)H, xe2x80x94CO2H, xe2x80x94C(xe2x95x90O)(Ra), xe2x80x94CO2(Ra), xe2x80x94SO3H, xe2x80x94S(O)0-2(Ra), xe2x80x94S(O)2NRaRb, xe2x80x94C(xe2x95x90O)N(Ra)O(Rb), xe2x80x94C(xe2x95x90O)N(Ra)2, xe2x80x94OC(xe2x95x90O)Ra, cycloalkyl, or aryl, wherein at each occurrence each of the groups Ra, Rb are independently selected from alkyl, substituted alkyl, heterocycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, and heterocyclo; or Ra and Rb taken together form a three-to-eight membered heterocyclo.
When the term xe2x80x9calkylxe2x80x9d is used to suffix another group, such as in xe2x80x9carylalkylxe2x80x9d, xe2x80x9cheterocycloalkylxe2x80x9d or cycloalkylalkyl,xe2x80x9d the term defines with more specifity at least one of the groups that a substituted alkyl will contain. In other words, in these instances the specifically-named groups are bonded directly through a substituted or unsubstituted alkyl chain as defined above. For example, an arylalkyl includes benzyl, and a heterocycloalkyl includes ethyl-morpholino or any other straight or branched hydrocarbon chain of 1 to 12 carbon atoms having a substituted or unsubstituted heterocyclo as one of its substituents.
The term xe2x80x9calkenylxe2x80x9d refers to straight or branched chain hydrocarbon groups of 2 to 10, preferably 2 to 4, carbon atoms having at least one double bond. Where an alkenyl group is bonded to a nitrogen atom, it is preferred that such group not be bonded directly through a carbon bearing a double bond. When reference is made to a substituted alkenyl, the alkenyl group will have one to three substituents as recited above for alkyl groups.
The term xe2x80x9calkynylxe2x80x9d refers to straight or branched chain hydrocarbon groups of 2 to 10, preferably 2 to 4, carbon atoms having at least one triple bond. Where an alkynyl group is bonded to a nitrogen atom, it is preferred that such group not be bonded directly through a carbon bearing a triple bond. A xe2x80x9csubstituted alkynylxe2x80x9d is substituted with one to three substituents as recited above for alkyl groups.
The term xe2x80x9calkylenexe2x80x9d refers to a chain bridge of 1 to 5 carbon atoms connected by single bonds {e.g., xe2x80x94(CH2)xxe2x80x94 wherein x is 1 to 5}, which may be branched with 1 to 3 lower alkyl groups.
The term xe2x80x9calkenylenexe2x80x9d refers to a chain bridge of 2 to 5 carbon atoms having one or two double bonds connected by single bonds and which may be branched with 1 to 3 lower alkyl groups. Exemplary alkenylene groups include xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94, xe2x80x94C(CH3)2CHxe2x95x90CHxe2x80x94 and xe2x80x94CH(C2H5)xe2x80x94CHxe2x95x90CHxe2x80x94.
The term xe2x80x9calkynylenexe2x80x9d refers to a chain bridge of 2 to 5 carbon atoms that has a triple bond therein, is connected by single bonds, and may be branched with 1 to 3 lower alkyl groups. Exemplary alkynylene groups include xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CH2xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CH(CH3)xe2x80x94Cxe2x89xa1Cxe2x80x94 and xe2x80x94Cxe2x89xa1Cxe2x80x94CH(C2H5)CH2xe2x80x94. When reference is made to a substituted alkylene, substituted alkenylene, or substituted alkynylene, these groups may have 1 to 3 substituents as defined above for alkyl groups.
The term xe2x80x9calkoxyxe2x80x9d refers to the group ORo, wherein the group Ro is selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclo, substituted alkyl, heterocycloalkyl, substituted alkenyl, or substituted alkynyl.
The term xe2x80x9caminoxe2x80x9d refers to xe2x80x94NH2, and the term xe2x80x9caminoalkylxe2x80x9d refers to xe2x80x94NRcRd, wherein Rc and Rd are independently selected from hydrogen, alkyl, substituted alkyl, heterocycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heterocyclo, and xe2x80x94C(xe2x95x90O)Re; or Rc and Rd are taken together to form a three-to-eight membered saturated or unsaturated heterocyclo ring which may have one to three substituents as defined below for heterocyclo groups. Re is selected from alkyl, substituted alkyl, heterocycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, and heterocyclo.
The term xe2x80x9calkylthioxe2x80x9d refers to an alkyl or substituted alkyl group as defined above being further substituted with one of the groups xe2x80x94SH or xe2x80x94SRs, wherein Rs is selected from alkyl, substituted alkyl, heterocycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, and heterocyclo.
The term xe2x80x9calkylamidexe2x80x9d refers to the group xe2x80x94C(xe2x95x90O)NRfRg, wherein Rf and Rg are independently selected from hydrogen, alkyl, substituted alkyl, heterocycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, and heterocyclo; or Rf and Rg taken together form a three-to-eight membered heterocyclo.
The terms xe2x80x9carxe2x80x9d or xe2x80x9carylxe2x80x9d refer to aromatic cyclic groups, for example, 6 membered monocyclic, 10 membered bicyclic or 12 membered tricyclic ring systems, which contain 6 to 14 carbon atoms. Exemplary aryl groups include phenyl, naphthyl, biphenyl and anthracenyl. Whenever reference is made to an aryl group (including without limitation in these definitions and in the claims), unless otherwise specifically indicated the aryl may have one to three substituents selected from the group consisting of Ra, halo, cyano, nitro, amino, aminoalkyl, hydroxy, ORa, xe2x80x94SH, xe2x80x94C(xe2x95x90O)H, xe2x80x94CO2H, C(xe2x95x90O)(Ra), xe2x80x94CO2(Ra), xe2x80x94SO3H, xe2x80x94S(O)0-2(Ra), xe2x80x94S(O)2NRaRb, xe2x80x94C(xe2x95x90O)N(Ra)O(Rb), xe2x80x94C(xe2x95x90O)N(Ra)2, and xe2x80x94OC(xe2x95x90O)Ra wherein at each occurrence each of the groups Ra, Rb are independently selected from alkyl, substituted alkyl, heterocycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, and heterocyclo, or taken together form a substituted or unsubstituted heterocyclo.
The term xe2x80x9ccycloalkylxe2x80x9d refers to fully saturated and partially unsaturated cyclic hydrocarbon groups of 3 to 12 carbon atoms. Cycloalkyl groups may be bicyclic, e.g., such as in bicycloheptane and bicyclooctane. Whenever reference is made to a cycloalkyl (including without limitation in these definitions and in the claims), unless otherwise specifically indicated the cycloalkyl may have one to three substituents selected from the group consisting of Ra, halo, cyano, nitro, amino, aminoalkyl, hydroxy, ORa, xe2x80x94SH, keto (xe2x95x90O), xe2x80x94C(xe2x95x90O)H, xe2x80x94CO2H, xe2x80x94C(xe2x95x90O)(Ra), xe2x80x94CO2(Ra), xe2x80x94SO3H, xe2x80x94S(O)0-2(Ra), xe2x80x94S(O)2NRaRb, xe2x80x94C(xe2x95x90O)N(Ra)O(Rb), xe2x80x94C(xe2x95x90O)N(Ra)2, and xe2x80x94OC(xe2x95x90O)Ra, wherein at each occurrence each of the groups Ra, Rb are independently selected from alkyl, substituted alkyl, heterocycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, and heterocyclo, or taken together form a heterocyclo.
The terms xe2x80x9chalogenxe2x80x9d and xe2x80x9chaloxe2x80x9d refer to fluorine, chlorine, bromine and iodine.
The terms xe2x80x9cheterocyclexe2x80x9d, xe2x80x9cheterocyclicxe2x80x9d or xe2x80x9cheterocycloxe2x80x9d refer to fully saturated or unsaturated, including aromatic (i.e. xe2x80x9cheteroarylxe2x80x9d) cyclic groups, for example, 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring systems, which have at least one heteroatom in at least one carbon atom-containing ring, and each ring of the heterocyclo is optionally substituted as defined below. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system. Each ring of the heterocyclic group may have one or more (preferably one or two) substitutents selected from Ra, halo, cyano, nitro, amino, aminoalkyl, hydroxy, ORa, xe2x80x94SH, keto (xe2x95x90O), xe2x80x94C(xe2x95x90O)H, xe2x80x94CO2H, xe2x80x94C(xe2x95x90O)(Ra), xe2x80x94CO2(Ra), xe2x80x94SO3H, xe2x80x94S(O)0-2(Ra), xe2x80x94S(O)2NRaRb, xe2x80x94C(xe2x95x90O)N(Ra)O(Rb), xe2x80x94C(xe2x95x90O)N(Ra)2, xe2x80x94OC(xe2x95x90O)Ra, wherein at each occurrence each of the groups Ra, Rb are independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, monocyclic heterocycloalkyl or monocyclic heterocyclo, or taken together form a heterocyclo.
Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, triazolyl, triazinyl, and the like. The term xe2x80x9cdiazapinexe2x80x9d refers to a heterocyclo having at least one seven atom ring with two nitrogen atoms in said seven atom ring.
Exemplary bicyclic heterocyclic groups include indolyl, benzothiazolyl, benzoxazolyl, benzodioxolyl, benzothienyl, quinuclidinyl, quinolinyl, tetra-hydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), tetrahydroquinolinyl and the like.
Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like.
The term xe2x80x9cheteroarylxe2x80x9d refers to aromatic heterocyclic groups.
Exemplary heteroaryl groups include pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furyl, thienyl, oxadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, triazinyl, and the like.
When reference is made to specifically-named heterocyclo, such as 1,2,3,4-tetrahydroquinoline, triazaspirodecane, morpholine, piperidine, pyrrolidine, thienyl, oxazole, and diazapine, and so forth, these rings may have one or more substituents as defined above for heterocyclo groups.
The term xe2x80x9cunsaturated ringxe2x80x9d includes partially or fully unsaturated and aromatic rings. When reference is made to an unsaturated heterocyclo, this means at least one ring of the heterocyclo is unsaturated (partially or fully), i.e., in a bicyclic or tricyclic heterocyclo, only one ring of the heterocyclo need be at least partially unsaturated to comprise an unsaturated heterocyclo as defined herein.
Included within compounds of formula (I) are those compounds where A and B comprise carbon to define pyrrole-based compounds; where A is nitrogen and B is carbon to define pyrazole-based compounds; and where A is carbon and B is nitrogen to define imidazole-based compounds, as further defined below. One skilled in the field may make appropriate selections to provide stable compounds.
Pyrrole-based Compounds
Compounds of formula (I) include pyrrole-based compounds useful as cannabinoid receptor modulators having formula (II), and pharmaceutically-acceptable salts thereof: 
in which
one of R5 and the group xe2x80x94C(xe2x95x90O)NR1R2 is attached to atom C-2 and the other of R5 and the group xe2x80x94C(xe2x95x90O)NR1R2 is attached to atom C-3 of the pyrrole ring;
R1 and R2 are independently selected from hydrogen, alkyl, substituted alkyl, heterocycloalkyl, cycloalkyl, aryl, and heterocyclo; or R2 together with R1 forms a heterocyclo; or R2 and R5 form a heterocyclo and R1 is hydrogen, alkyl, substituted alkyl, heterocycloalkyl, cycloalkyl, aryl, or heterocyclo;
R3 is hydrogen, alkyl, substituted alkyl, heterocycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heterocyclo, or alkoxy, or forms a heterocyclo with R4a;
R4a and R4b are (i) selected from hydrogen, alkyl, substituted alkyl, heterocycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heterocyclo, hydroxy, alkoxy, amino, aminoalkyl, cyano, halogen, alkylamide, NR8C(xe2x95x90O)R9, and S(O)uR10; or (ii) taken together form a fused six-membered aryl or heteroaryl having three or four R6;
R5 is hydrogen, alkyl, substituted alkyl, heterocycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, aryl, or heterocyclo; or R5 is taken together with R2 to form a heterocyclo;
R6 at each occurrence is selected independently of each other R6 from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted aryl, heterocyclo, hydroxy, alkoxy, amino, aminoalkyl, cyano, halogen, alkylamide, nitro, NR8C(xe2x95x90O)R9, S(O)uR10, xe2x80x94C(xe2x95x90O)R8, xe2x80x94CO2R8, xe2x80x94S(O)2NR8R10, xe2x80x94C(xe2x95x90O)N(R8)O(R9), xe2x80x94C(xe2x95x90O)NR8R9, and xe2x80x94OC(xe2x95x90O)R10; or one group R6 forms a heterocyclo with R3 and each other R6 is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted aryl, heterocyclo, hydroxy, alkoxy, amino, aminoalkyl, cyano, halogen, alkylamide, nitro, NR8C(xe2x95x90O)R9, S(O)uR10, xe2x80x94C(xe2x95x90O)R8, xe2x80x94CO2R8, xe2x80x94S(O)2NR8R10, xe2x80x94C(xe2x95x90O)N(R8)O(R9), xe2x80x94C(xe2x95x90O)NR8R9, and xe2x80x94OC(xe2x95x90O)R10;
R8 and R9 at each occurrence independent of each other R8 and R9 are selected from hydrogen, alkyl, substituted alkyl, heterocycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, and heterocyclo; or R8 and R9 taken together form a three-to-eight membered heterocyclo; or R8 together with R10 forms a three-to-eight membered heterocyclo; and
R10 at each occurrence independent of each other R10 is selected from alkyl, substituted alkyl, heterocycloalkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl, or forms a heterocyclo with R8, and u is 0, 1, 2 or 3.
Accordingly, included within compounds of formula (II) are cannabinoid receptor modulators comprising 2-carboxamide and 3-carboxamide pyrroles, e.g., compounds having formula (IIa) or (IIb), and pharmaceutically-acceptable salts thereof: 
wherein
R1 and R2 are (i) independently selected from hydrogen, alkyl, substituted alkyl, heterocycloalkyl, aryl, cycloalkyl, and heterocyclo; or (ii) taken together form a heterocyclo that is unsaturated or selected from optionally-substituted 1,2,3,4-tetrahydroquinoline, triazaspirodecane, morpholine, piperidine, pyrrolidine, and diazapine;
R3is hydrogen, alkyl, substituted alkyl, heterocycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, or heterocyclo;
R4a and R4b are independently selected from hydrogen, alkyl, substituted alkyl, heterocycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heterocyclo, hydroxy, alkoxy, amino, aminoalkyl, cyano, halogen, alkylamide, NR8C(xe2x95x90O)R9, and S(O)uR10;
R5 is hydrogen, alkyl, substituted alkyl, heterocycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkyny, alkoxy, aryl, or heterocyclo; and
R10 is alkyl, substituted alkyl, heterocycloalkyl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and u is 0, 1, 2 or 3.
With respect to compounds of formulae (IIa) and (IIb) useful as cannabinoid receptor modulators, 3-carboxamide pyrroles are preferred. Additionally, advantageously R1 is alkyl, substituted alkyl, heterocycloalkyl, aryl, cycloalkyl, or heterocyclo, and R2 is hydrogen or C1-3alkyl. R3 is preferably heterocycloalkyl (particularly morpholinylethyl), and R4a and R4b are hydrogen, halogen, lower alkyl, or alkoxy (more preferably C1-5alkoxy, OPh, or OBn). Also preferred are those carboxamide pyrroles where R1 is xe2x80x94CHR17R18, wherein R17 and R18 are selected from substituted alkyl, xe2x80x94CO2(alkyl), and alkylamide, or where R17 and R18 together form a cycloalkyl, an aryl, or a heterocyclo wherein said heterocyclo has sulfur or at least one of nitrogen and oxygen as its heteroatom(s).
Further included within compounds of formula (II) are compounds comprising bicyclic or tricyclic ringed systems having formula (IIc) or (IId), and pharmaceutically-acceptable salts thereof: 
wherein J, L, M and Q are carbon or nitrogen, provided that only one of J, L, M and Q is nitrogen;
R1, R2, R3, R5 and R6 are as defined above for compounds of formula (II), provided that when R3 forms a ring with one of R6, Q is carbon and R2 is selected independently of R5; and h is 3 or 4.
In compounds of formula (II), particularly (IIc) and (IId), when R1 and R2 together form a heterocyclo ring, advantageously said ring is unsaturated or is selected from optionally-substituted 1,2,3,4-tetrahydroquinoline, triazaspirodecane, morpholine, piperidine, pyrrolidine, and diazapine. When R1 and R2 independently comprise heterocyclo, advantageously said heterocyclo has as its heteroatom or heteroatoms either (i) sulfur or, (ii) at least one of nitrogen and oxygen. For example, R1 and R2 may independently comprise pyridine, pyrazole, imidazole, tetrazole, oxazole, oxadiazole, thiophene, morpholine, and so forth. Advantageously, R5 is not phenyl when attached to atom C-3 and at least one R6 is alkoxy (preferably Oxe2x80x94C1-5alkyl, OPh, or OBn), and two R6 groups are not simultaneously selected from amino and aminoalkyl.
Further included within compounds of formula (IIc) and (IId) are compounds comprising tricyclic ringed systems having formula (IIe) or (IIf), respectively, and pharmaceutically-acceptable salts thereof: 
wherein J, L, M, and Q are carbon or nitrogen, provided that only one of J, L, M and Q is nitrogen; R1, R2, R3, R5, R6, R8, R9 and R10 are as defined above for compounds of formula (IIa) and (IIb); R12 and R15 selected independently of each other are hydrogen, alkyl, substituted alkyl, heterocycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heterocyclo, hydroxy, alkoxy, amino, aminoalkyl, cyano, halogen, alkylamide, nitro, NR8C(xe2x95x90O)R9, S(O)uR10, keto (xe2x95x90O), xe2x80x94C(xe2x95x90O)R8, xe2x80x94CO2R8, xe2x80x94S(O)2NR8R10, xe2x80x94C(xe2x95x90O)N(R8)O(R9), xe2x80x94C(xe2x95x90O)NR8R9, or xe2x80x94OC(xe2x95x90O)R10; i is 2 or 3; and j is 2 or 4. In compounds of formula (II), including (IIa) through (IIe), as they appear the groups J, L, M, and Q are preferably carbon; preferably R1 is substituted alkyl and R2 is hydrogen or C1-3alkyl; R3 and R12 are xe2x80x94(CH2)nxe2x80x94Z or xe2x80x94Oxe2x80x94(CH2)nxe2x80x94Z, wherein Z is CH3, CO2H, amino, aminoalkyl, alkylamide, alkoxy, heterocyclo, aryl, or cycloalkyl, and n is 1 or 2; R5 and R15 are hydrogen, halogen, methoxy, or lower alkyl; and each R6 is hydrogen, alkoxy, lower alkyl, or halogen. More preferably, R3 and R12 are morpholinylC1-3alkyl.
Pyrazole-Based Compounds
Included within compounds of formula (I) are pyrazole-based compounds useful as cannabinoid receptor modulators having formula (III), and pharmaceutically-acceptable salts thereof: 
in which
R1 and R2 are (i) independently selected from hydrogen, alkyl, substituted alkyl, heterocycloalkyl, cycloalkyl, aryl, and heterocyclo; or (ii) taken together form a heterocyclo;
R3 is hydrogen, alkyl, substituted alkyl, heterocycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heterocyclo, or alkoxy; or forms a heterocyclo with R4a;
R4a and R4b are (i) selected from hydrogen, alkyl, substituted alkyl, heterocycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heterocyclo, hydroxy, alkoxy, amino, aminoalkyl, cyano, halogen, alkylamide, NR8C(xe2x95x90O)R9, and S(O)uR10; or (ii) taken together form a fused six-membered aryl or heteroaryl having three or four R6;
R6 at each occurrence is selected independently of each other R6 from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted aryl, heterocyclo, hydroxy, alkoxy, amino, aminoalkyl, cyano, halogen, alkylamide, nitro, NR8C(xe2x95x90O)R9, S(O)uR10, xe2x80x94C(xe2x95x90O)R8, xe2x80x94CO2R8, xe2x80x94S(O)2NR8R10, xe2x80x94C(xe2x95x90O)N(R8)O(R9), xe2x80x94C(xe2x95x90O)NR8R9, and xe2x80x94OC(xe2x95x90O)R10; or one group R6 forms a heterocyclo with R3 and each other R6 is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted aryl, heterocyclo, hydroxy, alkoxy, amino, aminoalkyl, cyano, halogen, alkylamide, nitro, NR8C(xe2x95x90O)R9, S(O)uR10, xe2x80x94C(xe2x95x90O)R8, xe2x80x94CO2R8, xe2x80x94S(O)2NR8R10, xe2x80x94C(xe2x95x90O)N(R8)O(R9), xe2x80x94C(xe2x95x90O)NR8R9, and xe2x80x94OC(xe2x95x90O)R10;
R8 and R9 at each occurrence independent of each other are selected from hydrogen, alkyl, substituted alkyl, heterocycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, and heterocyclo; or R8 and R9 taken together form a three-to-eight membered heterocyclo; or R8 together with R10 forms a three-to-eight membered heterocyclo; and
R10 is selected from alkyl, substituted alkyl, heterocycloalkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl, and u is 0, 1, 2 or 3.
Included within compounds of formula (III) are compounds comprising bicyclic ringed systems having formula (IIIa): 
wherein J, L, M and Q are carbon or nitrogen provided that only one of J, L, M and Q is nitrogen; R1, R2, R8, R9, and R10 are as defined above for compounds of formula (III); R3 is hydrogen, alkyl, substituted alkyl, heterocycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heterocyclo, or alkoxy; R6 at each occurrence is selected independently of each other R6 from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted aryl, heterocyclo, hydroxy, alkoxy, amino, aminoalkyl, cyano, halogen, alkylamide, nitro, NR8C(xe2x95x90O)R9, S(O)uR10, xe2x80x94C(xe2x95x90O)R8, xe2x80x94CO2R8, xe2x80x94S(O)2NR8R10, xe2x80x94C(xe2x95x90O)N(R8)O(R9), xe2x80x94C(xe2x95x90O)NR8R9, and xe2x80x94OC(xe2x95x90O)R10; and h is 3 or 4.
Advantageously, in compounds of formula (IIIa), J, L, M, and Q are carbon. In compounds of formula (III) and (IIIa), when R1 and R2 together form a heterocyclo ring, advantageously said ring is unsaturated or is selected from optionally-substituted 1,2,3,4-tetrahydroquinoline, triazaspirodecane, morpholine, piperidine, pyrrolidine, and diazapine; when R1 and R2 independently comprise heterocyclo, said heterocyclo has as its heteroatom or heteroatoms either (i) sulfur or, (ii) at least one of nitrogen and oxygen; and two R6 groups are not simultaneously selected from amino and amino alkyl. Preferably, R1 is substituted alkyl, and R2 is hydrogen or C1-3alkyl; R3 is morpholinyl C1-3alkyl; R5 and R15 are hydrogen, halogen, methoxy, or lower alkyl; and each R6 is selected from hydrogen, alkoxy, lower alkyl, or halogen.
Also included within compounds of formula (III) are compounds comprising bicyclic ringed systems having formula (IIIb): 
wherein R1, R2, R4b, R8, R9, and R10 are as defined above for compounds of formula (III); and R12 is selected from hydrogen, alkyl, substituted alkyl, heterocycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted aryl, heterocyclo, hydroxy, alkoxy, amino, aminoalkyl, cyano, halogen, alkylamide, nitro, NR8C(xe2x95x90O)R9, S(O)uR10, xe2x80x94C(xe2x95x90O)R8, xe2x80x94CO2R8, xe2x80x94S(O)2NR8R10, xe2x80x94C(xe2x95x90O)N(R8)O(R9), xe2x80x94C(xe2x95x90O)NR8R9, and xe2x80x94OC(xe2x95x90O)R10. Preferably, R12 is (CH2)nxe2x80x94Z, wherein Z is CH3, CO2H, amino, aminoalkyl, alkylamide, alkoxy, aryl, cycloalkyl, or heterocyclo (preferably morpholinyl), and n is 1 or 2.
Imidazole-Based Compounds
Also included within compounds of formula (I) are imidazole-based compounds having formula (IV), or pharmaceutically-acceptable salts thereof: 
in which
R1 and R2 are independently selected from hydrogen, alkyl, substituted alkyl, heterocycloalkyl, aryl, cycloalkyl, and heterocyclo; or taken together form a heterocyclo;
R3 is hydrogen, alkyl, substituted alkyl, heterocycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, or heterocyclo;
R4 is hydrogen, alkyl, substituted alkyl, heterocycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heterocyclo, hydroxy, alkoxy, amino, aminoalkyl, cyano, halogen, alkylamide, NR8C(xe2x95x90O)R9, or S(O)uR10;
R5 is hydrogen, alkyl, substituted alkyl, heterocycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, aryl, or heteroaryl; and
R10 is alkyl, substituted alkyl, heterocycloalkyl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and u is 0, 1, 2 or 3.
In compounds of formula (IV), advantageously R1 is substituted alkyl (more preferably CHR17R18, as defined herein); R2 is hydrogen or C1-3alkyl; R3 is xe2x80x94(CH2)nxe2x80x94Z, wherein Z is CH3, CO2H, amino, aminoalkyl, alkylamide, alkoxy, aryl, cycloalkyl, or heterocyclo (preferably morpholinyl), and n is 1 or 2; and R4 and R5 are hydrogen, halogen, methoxy, or lower alkyl.
When reference is made herein to compounds of formula (I), such reference includes compounds of formulae (II), (III) and (IV). Compounds of formula (I) include salts, prodrugs and solvates. The term xe2x80x9csalt(s)xe2x80x9d as employed herein denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases. Zwitterions (internal or inner salts) are included within the term xe2x80x9csalt(s)xe2x80x9d as used herein (and may be formed, for example, where the R substituents comprise an acid moiety such as a carboxyl group). Also included herein are quaternary ammonium salts such as alkylammonium salts. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are contemplated as within the scope of the invention as they may be useful, for example, in isolation or purification steps employed during preparation. Salts of the compounds of the formula (I) may be formed, for example, by reacting a compound of formula (I) with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates, toluenesulfonates, undecanoates, and the like.
Exemplary basic salts (formed, for example, where the R substituents comprise an acidic moiety such as a carboxyl group) include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines, N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. The basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.
Prodrugs and solvates of the compounds of the invention are also contemplated herein. The term xe2x80x9cprodrugxe2x80x9d as employed herein denotes a compound which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of the formula (I), or a salt and/or solvate thereof. Solvates of the compounds of formula (I) are preferably hydrates.
All stereoisomers of the present compounds, such as those which may exist due to asymmetric carbons on the R substituents of the compound of formula (I), including enantiomeric and diastereomeric forms, are contemplated within the scope of this invention. Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
According to the invention, cannabinoid receptor modulators, including compounds of formula (I), are typically employed as part of a pharmaceutical composition including a pharmaceutically-acceptable carrier for treating respiratory and/or non-respiratory diseases. The pharmaceutical compositions comprising at least one cannabinoid receptor modulator for treating respiratory disease and/or comprising compounds of formula (I), may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques such as those well known in the art of pharmaceutical formulation.
The cannabinoid receptor modulators for treating respiratory disease and/or compounds of formula (I) may be administered by any suitable means, for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally, such as in the form of suppositories; and in dosage unit formulations containing non-toxic, pharmaceutically-acceptable vehicles or diluents. The cannabinoid receptor modulators may, for example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release may be achieved by the use of suitable pharmaceutical compositions comprising the cannabinoid receptor modulators, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps. The cannabinoid receptor modulators may also be administered in the form of liposomes.
Exemplary compositions for oral administration include suspensions which may contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate release tablets which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and/or lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants such as those known in the art. The cannabinoid receptor modulators, including those for treating respiratory disease and/or compounds of formula (I), may also be delivered through the oral cavity by sublingual and/or buccal administration. Molded tablets, compressed tablets or freeze-dried tablets are exemplary forms which may be used. Exemplary compositions include those formulating the cannabinoid receptor modulators with fast dissolving diluents such as mannitol, lactose, sucrose and/or cyclodextrins. Also included in such formulations may be high molecular weight excipients such as celluloses (avicel) or polyethylene glycols (PEG). Such formulations may also include an excipient to aid mucosal adhesion such as hydroxy propyl cellulose (HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxy methyl cellulose (SCMC), maleic anhydride copolymer (e.g., Gantrez), and agents to control release such as polyacrylic copolymer (e.g., Carbopol 934). Lubricants, glidants, flavors, coloring agents and stabilizers may also be added for ease of fabrication and use.
Exemplary compositions for nasal aerosol or inhalation administration include solutions in saline which may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and/or other solubilizing or dispersing agents such as those known in the art.
Exemplary compositions for parenteral administration include injectable solutions or suspensions which may contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer""s solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
Exemplary compositions for rectal administration include suppositories which may contain, for example, a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
Exemplary compositions for topical administration include a topical carrier such as Plastibase (mineral oil gelled with polyethylene).
The effective amount of a compound employed in the present invention may be determined by one of ordinary skill in the art, and includes exemplary dosage amounts for an adult human of from about 0.1 to 100 mg/kg of body weight of active compound per day, which may be administered in a single dose or in the form of individual divided doses, such as from 1 to 4 times per day. It will be understood that the specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the species, age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion, drug combination, and severity of the particular condition. Preferred subjects for treatment include animals, most preferably mammalian species such as humans, and domestic animals such as dogs, cats and the like, subject to inflammatory, immunological, or respiratory cell-associated diseases and disorders.
Particularly preferred compounds of the invention are compounds of formula (I) represented by the following structures: 
wherein:
R1 and R2 are independently selected from hydrogen, alkyl substituted alkyl heterocycloalkyl, cycloalkyl, aryl, or heterocyclo having at its heteroatom or heteratoms either sulfur or at least one of nitrogen and oxygen; or taken together form a heterocyclo that is unsaturated or selected from optionally-substituted 1,2,3,4-tetrahydroquinoline, triazaspirodecane, morpholine, piperidine, pyrrolidine, and diazapine;
R3 and R12 are xe2x80x94(CH2)nxe2x80x94Z or xe2x80x94Oxe2x80x94(CH2)nxe2x80x94Z;
R4, R4a, R4b and R6 at each occurrence are selected from hydrogen, halogen, C1-6alkyl, cyano, nitro, hydroxy, alkoxy, and phenyl;
R5 is hydrogen, methyl, or ethyl;
R6a is hydrogen or OR8, wherein R8 is hydrogen, C1-6alkyl, aryl, or arylalkyl;
R15 is hydrogen, halogen, or alkyl;
Z is CH3, CO2H, amino, aminoalkyl, alkylamide, alkoxy, heterocyclo, aryl, or cycloalkyl,
h is 4;
i is 3; and
n is 1 or 2.
More preferred compounds are those represented by the above-referenced structures, wherein
R1 is substituted alkyl or forms a heterocyclo with R2 that is unsaturated or selected from optionally-substituted 1,2,3,4-tetrahydroquinoline, triazaspirodecane, morpholine, piperidine, pyrrolidine, and diazapine;
R2 is hydrogen, methyl, ethyl, or propyl, or forms a heterocyclo with R1 that is unsaturated or selected from optionally-substituted 1,2,3,4-tetrahydroquinoline, triazaspirodecane, morpholine, piperidine, pyrrolidine, and diazapine;
R3 and R12 are xe2x80x94(CH2)nxe2x80x94Z;
R4, R4a, R4b and R6 at each occurrence are selected from hydrogen, halogen, C1-4alkyl, hydroxy, and alkoxy;
R5 is hydrogen or methyl;
R6a is hydrogen or OR8, wherein R8 is hydrogen, C1-6alkyl, aryl, or arylalkyl;
R15 is hydrogen, halogen, or C1-2alkyl;
Z is heterocyclo;
n is 1 or 2;
h is 4; and
i is 3.
Further preferred compounds are those represented by the above-preferred structures, wherein
R1 is xe2x80x94CHR17R18;
R2 is hydrogen or methyl;
R3 and R12 are (CH2)n-morpholinyl;
R4, R4a, R4b and R6 at each occurrence are selected from hydrogen, C1-4alkyl, hydroxy, and alkoxy;
R5 is hydrogen or methyl;
R6a is hydrogen or OR8, wherein R8 is hydrogen, C1-5alkyl, phenyl, or benzyl;
R15 is hydrogen, halogen, or C1-4alkyl;
R17 and R18 are (i) selected independently from hydrogen and xe2x80x94(CH2)sxe2x80x94(CR21R22)vxe2x80x94(CH2)txe2x80x94W; or (ii) R17 and R18 together form cycloalkyl, aryl, or heterocyclo having as its heteroatom or heteroatoms sulfur or at least one of oxygen and nitrogen;
W at each occurrence is selected independently from CH3, alkylamide, aminoalkyl, alkylthio, alkoxy, hydroxy, cyano, xe2x80x94CO2R19, xe2x80x94C(xe2x95x90O)R19, xe2x80x94C(xe2x95x90O)N(R19)O(R20), xe2x80x94NR19(Cxe2x95x90O)R20, aryl, cycloalkyl, and heterocyclo having as its heteroatom or heteroatoms sulfur or at least one of oxygen and nitrogen;
R19 and R20 are selected from hydrogen, alkyl, substituted alkyl, heterocycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, and heterocyclo;
R21 and R22 are hydrogen, alkyl, hydroxy, or hydroxyalkyl;
h is 4;
i is 3;
n is 1 or 2;
s and t are 0, 1 or 2; and
v is 0 or 1.
Also preferred are compounds as immediately defined above where R17 and R18 are (i) xe2x80x94(CH2)sxe2x80x94W, wherein W at each occurrence is selected from xe2x80x94CH3, C1-4alkylthio, C1-4alkoxy, hydroxy, xe2x80x94CO2H, xe2x80x94CO2C1-4alkyl, xe2x80x94C(xe2x95x90O)N(C1-4alkyl)2, xe2x80x94C(xe2x95x90O)NH(C1-4alkyl), xe2x80x94C(xe2x95x90O)NH(cycloalkyl), xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)C1-4alkyl, xe2x80x94C(xe2x95x90O)N(C1-4alkyl)O(C1-4alkyl), xe2x80x94NH(Cxe2x95x90O)C1-4alkyl, xe2x80x94N(C1-4alkyl)(aryl), xe2x80x94NH(Cxe2x95x90O)aryl, phenyl, imidazole, biphenyl, pyridine, pyrrolidine, thiophene, pyrazole, imidazole, tetrazole, oxazole, oxadiazole, and napthyl, wherein said group W is optionally substituted with one to four groups selected from C1-4alkyl, hydroxy, halogen, C1-4alkoxy, trifluoromethyl, amino, acetylamino, heterocyclo, benzyl, or aryl; or (ii) taken together form a three-to-eight membered cycloalkyl or bicycloalkyl optionally substituted with one to four groups selected from C1-4alkyl, C1-4alkoxy, aryl, cycloalkyl, and heterocyclo.
Compounds of formula (I), cannabinoid receptor modulators illustrated in the Examples hereinafter, and intermediates for use in preparing the compounds of formula (I), may be prepared using the methods illustrated in the following Schemes A through N. Schemes A and B and G through J show schemes for preparing compounds of formula (I); schemes C through F show methods for preparing compounds useful as cannabinoid receptor modulators and as intermediates in preparing compounds of formula (I); schemes K through M describe in more detail inventive processes claimed herein for preparing compounds of formula (I); and scheme N illustrates a general procedure for Pd catalyzed indole cyclizations useful in preparing compounds of formula (I). For all of the schemes and compounds, the groups A, B, J, L, M, Q, R1-R6, R15, and R16, are as described above for a compound of formula I, unless otherwise indicated. Suitable selections may be made by one skilled in the field of appropriate groups for each of the groups X, R*, Rxe2x80x2, Rxe2x80x3, Ra, Rb or other groups generally referenced in these schemes. Solvents, temperatures, pressures, and other reaction conditions also may readily be selected by one of ordinary skill in the art. All documents cited are incorporated herein by reference in their entirety, and abbreviations that appear hereinafter are used in these schemes for ease of reference. Starting materials are commercially available or can be readily prepared by one of ordinary skill in the art.
The methods described herein may be carried out with starting materials and/or reagents in solution or alternatively, where appropriate, with one or more starting materials or reagents bound to a solid support {see (1) Thompson, L. A. and Ellman, J. A., Chemical Reviews, 96, pp. 555-600 (1996); (2) Terrett, N. K., et al, Tetrahedron, 51, pp. 8135-8173 (1995); (3) Gallop, M. A. et al, Journal of Medicinal Chemistry, 37, 1233-1251 (1994); (4) Gordon, E. M. et al, Journal of Medicinal Chemistry, 37, pp. 1385-1401 (1994); (5) Balkenhohl, F., et al, Angewandte Chemie International Edition in English, 35, pp. 2288-2337 (1996); (6) Balkenhohl, F. et al, Angewandte Chemie, 108, pp. 2436-2487 (1996); and (7) Sofia, M. J., Drugs Discovery Today, 1, pp. 27-34 (1996)}. 
Starting compound (1), wherein A and B are nitrogen or carbon and R* is a carboxyl protecting group such as alkyl or arylalkyl, can be treated with a base and an alkylating agent. Exemplary bases include LDA, K2CO3, sodium hydride, and sodium/potassium hexamethyldisilazide, and exemplary alkylating agents include R3X where X is a leaving group, such as a halogen or a triflate, and R3 is preferably alkyl, arylalkyl, cycloalkylalkyl, or heterocycloalkyl. Saponification with an aqueous base such as LiOH then gives compound (2).
Compound (2) may be reacted with an amine using reaction conditions well known in the art for peptide bond synthesis {see, for example, Bodanszky and Bodanszky, The Practice of Peptide Chemistry, Springer-Verlag (1984); Bodanszky, Principles of Peptide Synthesis, Springer-Verlag (1984)} to give a compound of formula (I). Exemplary reagents for activating the carboxyl group of compound (2) for reacting with the amine include BOP chloride, BOP reagent, HATU, carbodiimides such as DCC and EDC, either alone or in combination with a hydroxybenzotriazole.
Alternatively, compound (1) can be isolated and then treated with an appropriate amine in a nonprotic solvent such as THF or DMF in the presence of base, for example, an organic base such as TEA, DIPEA, DBU, or sodium/potassium hexamethyldisilazide, or an inorganic base such as sodium, potassium or cesium carbonate or sodium or potassium hydride.
Alternatively, compound (2) may be prepared, for example, by reaction with thionyl chloride or oxalyl chloride, followed by subsequent reaction with an amine to provide a compound of formula (I).
Compound (1) is commercially available or may be readily prepared by one skilled in the field, or where A and B are carbon may be prepared as described below in Scheme J. 
Starting compound (1) can be saponified followed by treatment with an amine under standard amide bond forming conditions (described above in Scheme A) to give compound (4). Treatment of compound (4) with a suitable base and an alkylating agent R3X (as described above for Scheme A) gives a compound of formula (I). 
Schemes C and D set forth methods for preparing pyrrole-based fused heterocylic compounds (10) which may be used as starting materials (1) in Schemes A and B, i.e. where two R4 groups form a fused ring. These compounds (10) may be used to form compounds of formula (I). Alternatively, compounds of formula (10) may be used in Scheme H, below, to form compounds of formula (Ib) or (Ic).
Compound (9) can be prepared alternatively from compounds (5), (6), (7) or (8) as follows:
(i) from compound (5) by treatment with beta ketochlorosulfides and a base such as TEA followed by desulfurization using raney nickel (Gassman et al. Journal of the American Chemical Society, Vol. 96, pp. 5512-5517 (1974);
(ii) from compound (6) by treatment with an aniline protecting group such as Boc followed by treatment with an organolithium such as sec-BuLi and an o-methyl hydroxamate;
(iii) from compound (7) by treatment with a nitroalkane followed by acetylation and hydrogenation; or
(iv) from compound (8) by treatment with an alkylamide dimethyl acetal (such as N,N-dimethyl acetamide dimethyl acetal) followed by hydrogenation.
Compound (9) can be converted to compound (10) by treatment with a base such as methyl magnesium bromide and an alkyl chloroformate such as ethyl chloroformate.
Alternatively, compound (9) can be converted to compound (10) by treatment with trichloromethyl acid chloride and base such as collidine followed by conversion to an alkyl ester with an alkoxide (such as KOH) and an alcohol (such as MeOH). 
As an alternative to scheme C, compound (10) can be prepared directly from compound (7) by treatment with a Wittig reagent such as (ii) followed by reduction/cyclization. 
Schemes E and F describe methods for preparing pyrazole-based compounds (17), which may used to make compounds of formula (I) in accordance with the methods of Schemes A and B.
Compound (17) can be prepared from compound (11) or compound (12), e.g., via base-catalyzed hydrolysis of either compound (15) or compound (16).
Compound (11) can be converted to compound (14) via a one-carbon extension sequence (e.g., carboxylation with base and a suitable agent followed by an amide bond coupling). Compound (14) can be converted to compound (15) upon treatment with a nitroso agent, such as sodium nitrite or tert-butyl nitrite. Compound 12 can be converted to compound (16) under the same conditions.
Compound (12) can be prepared from compound (11) or compound (13), i.e., from compound (11) via a one-carbon extension sequence (carboxylation with base and a suitable agent) or from compound (13) via a two-carbon extension sequence (alkylation with base and a suitable agent). 
Alternatively to Scheme E, compound (17) can be prepared from compound (18) as shown in Scheme F, i.e., by conversion of compound (18) to compound (19) via base-catalyzed ring opening followed by diazotization, reduction of compound (19) to compound (20), and ring closure of compound (20) to give compound (17). 
Compounds of formula (Ia) wherein A is nitrogen or carbon can be prepared from compound (21) as shown in Scheme G. Compound (21) can be N-protected and unmasked (removal of O-benzyl or O-methyl) to give compound (22). O-alkylation of compound (22) gives compound (23).
Compound (23) can be converted to compound (25) directly via a three-step sequence: a) reaction with a suitable amine; b) removal of N-protecting group; and c) cyclization under Mitsunobu conditions. xe2x80x9cMitsunobu conditionsxe2x80x9d are known in the field and defined in Oyo Mitsunobu, xe2x80x9cThe Use of Diethyl Azodicarboxylate and Triphenylphosphine in Synthesis and Transformation of Natural Productsxe2x80x9d, Synthesis (1981), pp 1-28, which is incorporated herein by reference. Alternatively, compound (23) can be converted to compound (25) via compound (24), i.e., treatment of compound (23) with a suitable amine followed by mesylation of alcohol moiety gives compound (24), and removal of the N-protecting group of compound (24) followed by ring closure gives compound (25).
Base-catalyzed hydrolysis of compound (25) followed by an amide bond coupling reaction with a suitable amine provides compound of formula (Ia). 
Scheme H describes the preparation of compounds of formula (Ic) starting with compounds of formula (10) (see Scheme C), and the methods of Schemes A and B. Compound (10) can be saponified followed by treatment with an amine under standard amide bond forming conditions (described in Scheme A) to give a compound (Ib), also a compound of formula (I). Compound (Ic) can be prepared from compound (Ib) by treatment with an organolithium (such as n-BuLi) followed by an aldehyde derivative R2CHO, followed by treatment with an aqueous acid such as HCl (see, e.g., Clark, R. D. et al, Journal of Medicinal Chemistry, Vol. 36 (1993), pp. 2645-2657) (xe2x80x9cClarkxe2x80x9d). 
Scheme I illustrates methods for preparing compounds of formulae (Ie), (If), and (Ig) from compound (Id). Compound (Ie) can be prepared from compound (Id) by treatment with NCS or SELECTFLUOR(trademark). Compound (If) can be prepared from compound (Id) by treatment with NBS. Compound (Ig) can be prepared from compound (If) by treatment with an organolithium (such as t-BuLi) followed by treatment with an alkyl halide R16X or tosyl cyanide (TsCN).
Compound (Id) can be prepared from Scheme H, wherein R15 is hydrogen. 
Scheme J describes the formulation of compounds of formula (Ih) and (Ii). Compound (28) can be prepared by heating a mixture compound (26) and (27). Compound (1) can be prepared from compound (28) by treatment with a palladium catalyst such as Pd(PPh3)4, an inorganic base such as K2CO3, and an aryl halide such as mesitylene bromide {see, e.g., Aoyagi, et al. Tetrahedron Letters, 37, 9203-9206 (1996)}. Compound (1) can be saponified followed by treatment with an amine under standard amide bond forming conditions (described above in Scheme A) to give a compound of formula (Ih). Compound of formula (Ii) can be prepared from compound (Ih) by treatment with an organolithium (such as n-butyllithium) followed by an aldehyde derivative R5CHO followed by treatment with an aqueous acid such as HCl (see, e.g Clark, cited above in Scheme H). 
Scheme K describes an inventive process for making compounds of formula (Ij). Compound (7a) may be produced by reacting compound (7) (see Scheme C) with a nitro alkyl under appropriate conditions such as in the presence of a halide salt (e.g. potassium fluoride) and a crown ether (e.g. 18-crown-6).
Compound (7a) can be converted to a leaving group such as with acetic anhydride in sodium acetate and a fluoride-containing agent such as KF in the presence of 18-crown-6 to give a compound (7b).
Compound (7b) can be reduced under standard hydrogenation conditions (e.g. H2/Pd/C) in a suitable solvent such as EtOH/AcOH/EtOAc to provide compound (9).
Compound (9) can be treated with R3-halide in the presence of a base such as NaOH and a suitable solvent such as DMSO to form a compound of formula (29).
Compound (29) can be treated with trihaloacetyl halide (e.g. where the halide is chloride) to give compound (30). In the case where R3 does not comprise a basic substituent, a suitable base such as collidine and a suitable solvent such as DCE are necessary to give compound (30). In the case where R3 contains a basic substituent, addition of an external base such as collidine is not needed.
Compound (30) can be treated with an appropriate amine in the presence of a suitable base to form amides of formula (Ij). Alternatively, compound (30) can be hydrolyzed to the carboxylate using a base such as NaOH followed by standard amide bond coupling methods known in the art to form compounds of formula (Ij). 
Scheme L shows an inventive process for preparing compounds of formula (Ik), wherein A is nitrogen or CR5 as defined herein.
The process comprises subjecting a compound (31) to alkylation {e.g. with (R)-(+)-glycidol under standard Mitsunobu conditions (DEAD, Ph3P)} to give compound (32). Alternatively, compound (31) can be reacted with (R)-(xe2x88x92)-epichalohydrin in base to give compound (32).
Compound (32) undergoes ring opening in the presence of a nucleophile R11xe2x80x94X1 (or R11xe2x80x94X1xe2x80x94H where H is hydrogen) wherein R11 is selected from alkylene, substituted alkylene, alkenylene, substituted alkenylene, cycloalkyl, aryl, and heterocyclo, and X1 (or X1xe2x80x94H) is any nucleophile which can ring open an epoxide including, but not limited to alcohols, amines, thiols, azides and carbon nucleophiles to give compound (33).
Compound (33) can undergo cyclization under Mitsunobu conditions (DEAD, PPh3) to give compound (34). Alternatively, compound (33) can be treated with a sulfonyl halide to provide a sulfonate which can cyclize to form compound (34).
Compound (34) can be treated with trihaloacetyl halide (e.g. trichloroacetyl chloride) under elevated temperatures (preferably from about 40 to 120xc2x0 C.) to give compound (35).
Compound (35) can be hydrolyzed under basic conditions to give compound (36). Compound (36) can be coupled to an amine using standard amide bond coupling techniques (EDC/HOBT or acid chloride) to give compounds of formula (Ik). 
Scheme M shows an inventive process for making compounds of formulae (Il) and (Im).
The process comprises reacting compound (37) with an alkyl lithium and carbon dioxide to form compound (38).
Compound (38) is reacted with a dialkyl amine under standard amide bond conditions (such as EDCI, HOBt) to form compound (39).
Compound (39) is treated with a nitrite such as NaNO2 in aqueous acid (such as acetic acid) at elevated temperatures (preferably from about 50 to 140xc2x0 C.) to give compound of formula (Il).
Compound of formula (Il) is treated with R3-halide in the presence of a base such as sodium hydride to give a compound of formula (Im), wherein R3 is other than hydrogen.
Compound of formula (Im) is hydrolyzed under aqueous basic conditions to form compound (41).
Compound (41) is coupled to an amine under standard amide bond coupling conditions (e.g. EDC/HOBT or acid chloride) to provide compounds of formula (In). 
Scheme N shows a general procedure for Pd-catalyzed indole cyclizations that can be used to make compounds of formula (Io) or cannabinoid receptor modulators or intermediates (45) for making compounds of formula (I).
A mixture of ortho-halo aniline (42) and beta-keto ester (43a) or amide (43b) (1.2 equiv) are heated with azeotropic removal of water in the presence of an acid catalyst for 24 h to give enamides (44a) or (44b).
Pd-catalyzed cyclization of enamides (44a) or (44b) is carried out using 10-20 mole % Pd and 21-42 mole % phosphine ligand to give compounds (45) or compounds of formula (Io). Tri-ortho tolyl phosphine is the preferred ligand. Isolation of the indoles can be performed by column chromatography.
Applicants have discovered that modulators to the cannabinoid receptor are effective for treating respiratory diseases. Respiratory diseases for which cannabinoid receptor modulators are useful include but are not limited to chronic pulmonary obstructive disorder, emphysema, asthma, and bronchitis. Such cannabinoid receptor modulators include each of the compounds described in the examples herein, including compounds of formula (I), as well as those compounds described Examples 1-2, 14-16, and 67-71 herein. Applicants"" discovery that cannabinoid receptor modulators are useful for treating respiratory diseases also pertains to cannabinoid receptor modulators previously identified as effective for other uses, such as cannabinoid receptor modulators described in European Patent Documents Nos. EP 0570920 and EP 0444451; International Publications Nos. WO 97/29079, WO 99/02499, WO 98/41519, and WO 9412466; U.S. Pat. Nos. 4,371,720, 5,081,122, 5,292,736, and 5,013,387; and French Patent No. FR 2735774.
Applicants also have discovered a group of novel cannabinoid receptor modulators of formula (I) useful for treating any cannabinoid-receptor mediated diseases, including the respiratory diseases referenced above and non-respiratory diseases. Exemplary non-respiratory cannabinoid receptor-mediated diseases include transplant rejection, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, lupus, graft v. host disease, T-cell mediated hypersensitivity disease, psoriasis, Hashimoto""s thyroiditis, Guillain-Barre syndrome, cancer, contact dermatitis, allergic rhinitis, and ischemic or reperfusion injury.
The compounds employed in the present invention for treatment of respiratory or non-respiratory diseases stimulate inhibitory pathways in cells, particularly in leukocytes, lung epithelial cells, or both, and are thus useful in treating such diseases. As used with reference to the utilities described herein, the term xe2x80x9ctreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d encompasses prevention, partial alleviation, or cure of the disease or disorder. xe2x80x9cLeukocyte activationxe2x80x9d is defined herein as any or all of cell proliferation, cytokine production, adhesion protein expression, and production of inflammatory mediators. xe2x80x9cEpithelial cell activationxe2x80x9d is defined herein as the production of any or all of mucins, cytokines, chemokines, and adhesion protein expression.
For example, CB2 receptor modulators are useful in treating a number of diseases mentioned above (for example, the treatment of inflammatory diseases), since CB2 receptor modulators prevent monocyte/macrophage activation and the release of inflammatory cytokines. The treatment of leukocyte-mediated diseases is one particularly preferred embodiment of the present invention through use of the compounds of formula (I). Compounds which selectively inhibit leukocyte activation and proliferation are preferred.
In addition, CB receptor modulators are useful in treating respiratory disorders. Such compounds block the activation of lung epithelial cells by moeties such as allergic agents, inflammatory cytokines or smoke, thereby limiting release of mucin, cytokines, and chemokines. Another preferred embodiment of the present invention comprises use of novel cannabinoid receptor modulator compounds to treat respiratory disease wherein the compounds selectively inhibit lung epithelial cell activation.
The cannabinoid receptor modulators for treating respiratory disease or non-respiratory diseases in accordance with the present invention may be used with other therapeutic agents such as those described below. Such other therapeutic agent(s) may be administered prior to, simultaneously with, or following the administration of the cannabinoid receptor modulators in accordance with the invention.
Exemplary of such other therapeutic agents which may be used in combination with cannabinoid receptor modulators include the following: cyclosporins (e.g., cyclosporin A), CTLA4-Ig, antibodies such as anti-ICAM-3, anti-IL-2 receptor (Anti-Tac), anti-CD45RB, anti-CD2, anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86, monoclonal antibody OKT3, agents blocking the interaction between CD40 and gp39, such as antibodies specific for CD40 and/or gp39 (i.e., CD154), fusion proteins constructed from CD40 and gp39 (CD40Ig and CD8gp39), inhibitors, such as nuclear translocation inhibitors, of NF-kappa B function, such as deoxyspergualin (DSG), non-steroidal antiinflammatory drugs (NSAIDs) such as ibuprofen, steroids such as prednisone or dexamethasone, gold compounds, antiproliferative agents such as methotrexate, FK506 (tacrolimus, Prograf), mycophenolate mofetil, cytotoxic drugs such as azathiprine and cyclophosphamide, TNF-xcex1 inhibitors such as tenidap, anti-TNF antibodies or soluble TNF receptor such as etanercept (Enbrel), rapamycin (sirolimus or Rapamune), leflunomide (Arava), and cyclooxygenase-2 (COX-2) inhibitors such as celecoxib (Celebrex) and rofecoxib (Vioxx), or derivatives thereof, anticytokines such as antiIL-4 or IL-4 receptor fusion proteins and PDE 4 inhibitors such as Ariflo, and the PTK inhibitors disclosed in the following U.S. patent applications, incorporated herein by reference in their entirety: Ser. No. 09/097,338, filed Jun. 15, 1998; Ser. No. 09/094,797, filed Jun. 15, 1998; Ser. No. 09/173,413, filed Oct. 15, 1998; and Ser. No. 09/262,525, filed Mar. 4, 1999. See also the following documents and references cited therein and incorporated herein by reference: Hollenbaugh, D., Et Al, xe2x80x9cCleavable CD40Ig Fusion Proteins and the Binding to Sgp39xe2x80x9d, J. Immunol. Methods (Netherlands), 188(1), pp. 1-7 (Dec. 15, 1995); Hollenbaugh, D., et al, xe2x80x9cThe Human T Cell Antigen Gp39, A Member of the TNF Gene Family, Is a Ligand for the CD40 Receptor: Expression of a Soluble Form of Gp39 with B Cell Co-Stimulatory Activityxe2x80x9d, EMBO J (England), 11(12), pp. 4313-4321 (December 1992); and Moreland, L. W. et al., xe2x80x9cTreatment of Rheumatoid Arthritis with a Recombinant Human Tumor Necrosis Factor Receptor (P75)-Fc Fusion Protein,xe2x80x9d New England J. of Medicine, 337(3), pp. 141-147 (1997).
The above other therapeutic agents, when employed in combination with the compounds of the present invention, may be used, for example, in those amounts indicated in the Physicians"" Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.
Use of the compounds of the present invention as encompassed by formula (I) in treating leukocyte activation-associated disorders is exemplified by, but is not limited to, treating a range of disorders such as: transplant (such as organ transplant, acute transplant, xenotransplant or heterograft or homograft (such as is employed in burn treatment)) rejection; protection from ischemic or reperfusion injury such as ischemic or reperfusion injury incurred during organ transplantation, myocardial infarction, stroke or other causes; transplantation tolerance induction; arthritis (such as rheumatoid arthritis, psoriatic arthritis or osteoarthritis); multiple sclerosis; respiratory and pulmonary diseases including but not limited to chronic obstructive pulmonary disease (COPD), emphysema, bronchitis, and acute respiratory distress syndrome (ARDS); inflammatory bowel disease, including ulcerative colitis and Crohn""s disease; lupus (systemic lupus erythematosis); graft vs. host disease; T-cell mediated hypersensitivity diseases, including contact hypersensitivity, delayed-type hypersensitivity, and gluten-sensitive enteropathy (Celiac disease); psoriasis; contact dermatitis (including that due to poison ivy); Hashimoto""s thyroiditis; Sjogren""s syndrome; Autoimmune Hyperthyroidism, such as Graves"" Disease; Addison""s disease (autoimmune disease of the adrenal glands); Autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome); autoimmune alopecia; pernicious anemia; vitiligo; autoimmune hypopituatarism; Guillain-Barre syndrome; other autoimmune diseases; glomerulonephritis; serum sickness; uticaria; allergic diseases such as respiratory allergies (asthma, hayfever, allergic rhinitis) or skin allergies; scleracierma; mycosis fungoides; acute inflammatory and respiratory responses (such as acute respiratory distress syndrome and ishchemia/reperfusion injury); dermatomyositis; alopecia areata; chronic actinic dermatitis; eczema; Behcet""s disease; Pustulosis palmoplanteris; Pyoderma gangrenum; Sezary""s syndrome; atopic dermatitis; systemic schlerosis; and morphea. The term xe2x80x9cleukocyte activation-associatedxe2x80x9d or xe2x80x9cleukocyte-activation mediatedxe2x80x9d disease as used herein includes each of the above referenced diseases or disorders. In a particular embodiment, the compounds of the present invention are useful for treating the aforementioned exemplary disorders irrespective of their etiology. The combined activity of the present compounds towards monocytes, macrophages, T-cells, etc. may be useful in treating any of the above-mentioned disorders.
Cannabinoid receptors are important in the regulation of Fc gamma receptor responses of monocytes and macrophages. Compounds of the present invention inhibit the Fc gamma dependent production of TNF alpha in human monocytes/macrophages. The ability to inhibit Fc gamma receptor dependent monocyte and macrophage responses results in additional anti-inflammatory activity for the present compounds. This activity is especially of value, for example, in treating inflammatory diseases such as arthritis or inflammatory bowel disease. In particular, the present compounds are useful for treating autoimmune glomerulonephritis and other instances of glomerulonephritis induced by deposition of immune complexes in the kidney that trigger Fc gamma receptor responses leading to kidney damage.
Cannabinoid receptors are expressed on lung epithelial cells. These cells are responsible for the secretion of mucins and inflammatory cytokines/chemokines in the lung and are thus intricately involved in the generation and progression of respiratory diseases. Cannabinoid receptor modulators regulate both the spontaneous and the stimulated production of both mucins and cytokines. Thus, such compounds are useful in treating respiratory and pulmonary diseases including, COPD, ARDS, and bronchitis.
Cannabinoid receptors may be expressed on gut epithelial cells and hence regulate cytokine and mucin production and may be of clinical use in treating inflammatory diseases related to the gut. Cannabinoid receptors are also expressed on lymphocytes, a subset of leukocytes. Thus, cannabinoid receptor modulators will inhibit B and T-cell activation, proliferation and differentiation. Thus, such compounds will be useful in treating autoimmune diseases that involve either antibody or cell mediated responses such as multiple sclerosis and lupus.
In addition, cannabinoid receptors regulate the Fc epsilon receptor and chemokine induced degranulation of mast cells and basophils. These play important roles in asthma, allergic rhinitis, and other allergic disease. Fc epsilon receptors are stimulated by IgE-antigen complexes. Compounds of the present invention inhibit the Fc epsilon induced degranulation responses, including the basophil cell line, RBL. The ability to inhibit Fc epsilon receptor dependent mast cell and basophil responses results in additional anti-inflammatory and anti-allergic activity for the present compounds. In particular, the present compounds are useful for treating asthma, allergic rhinitis, and other instances of allergic disease.
Membrane Binding Assay Using Human CB1 or CB2
The following assay has been carried out using the human cannabinoid receptor expressed in CHO cells.
Radioactive tracer label (WIN 55,212-2 Mesylate [5,7-3H] for CB2, CP55,940 for CB1) and test compound are incubated together in a 96-well tissue culture plate. All reagents are dissolved or resuspended in binding buffer (10 mM HEPES, pH 7.4, 1 mM EDTA, 5 mM MgCl2, 0.3% BSA). The reaction is initiated by the addition of membranes (50 ug) from CHO-K1 cells expressing either CB1 or CB2). The plates are incubated 2 hours with shaking at room temperature and the reaction is harvested on a Wallac Filtermat B with 7 wash cycles using wash buffer (10 mM HEPES, pH 7.4, 0.1% BSA). The filter is counted in a Betaplate scintillation counter to ascertain the cannabinoid inhibitory activity of the test compound (activity inversely proportional to the amount of labeled WIN-55212-2 incorporated). Routinely the radiolabel was used at a concentration of 10 nM but the exact concentration of reagents and the amount of label can be varied as needed.
This assay is advantageous as it can be conducted in a 96-well format that is readily automated. Different labeled cannabinoid ligands can be substituted into the assay. The recombinant cannabinoid receptors may be obtained from commercial sources and can be expressed in CHO or insect cell culture (Spodoptera frugiperda cells).
Cell Assays
(1) Monocyte/Macrophage cytokine production
Freshly isolated human monocytes, or the human monocytic cell line THP-1, are incubated at 1xc3x97106 cells/ml in RPMI 1640 media containing 10% FBS with the test compound for 30 minutes and then stimulated by the addition of either lipopolysaccharide (LPS) or immune complexes (IC). Cells are incubated for 6 h at 37xc2x0 C. at which time the cell supernatants are removed and assayed for cytokines (TNF, IL-1xcex2, IL-6, IL-8) using commercially available ELISA kits. The cannabinoid agonists inhibit the production of inflammatory cytokines.
(2) Activation of Lung Epithelial Cells
The ability of the cannabinoids to inhibit mucin, chemokine/cytokine production from lung epithelial cells is evaluated with human lung epithelial cell lines H292 and A549. Epithelial cells are cultured overnight in 48 well microtiter plates in complete RMPI 1650 (200 xcexcl/well) at a density of 2xc3x97105 cells/ml. The media is removed and replaced with fresh media. Test compounds in 50 xcexcl isotonic buffer are added and incubated for 1 hour at 37xc2x0 C. Cell activation is triggered by the addition of a stimulatory agent comprising one of EGF, smoke conditioned media, TNF-xcex1 or IL-1xcex2. In this assay, the IC50 for Win-55212-2 less than 20 mcM. After a desired period of time (e.g., 24 h) the cell supernatants are removed and assayed for mucin cytokine and chemokines by ELISA. The cannabinoid agonists inhibit mucin and IL-8 production from lung epithelial cells.
In addition to Win-55212-2 (described in French Patent document FR 2,735774 A1, incorporated herein), compounds of formula (I) demonstrated activity in the above lung epithelial cell assay, particularly indole and indazole-based amino acid esters described herein.
(3) T cell Proliferation Assays
The ability of the cannabinoids to inhibit the proliferation of normal human peripheral blood T cells that have been stimulated to grow with anti-CD3 plus anti-CD28 antibodies is evaluated. A 96 well plate is coated with a monoclonal antibody to CD3 (such as G19-4), the antibody is allowed to bind, and then the plate is washed. The antibody bound to the plate serves to stimulate the cells. Normal human peripheral blood T cells are added to the wells along with test compound plus anti-CD28 antibody to provide co-stimulation. After a desired period of time (e.g., 3 days), the [3H]-thymidine is added to the cells, and after further incubation to allow incorporation of the label into newly synthesized DNA, the cells are harvested and counted in a scintillation counter to measure cell proliferation.
(4) Degranulation of RBL-cells
RBL 2H3 cells are cultured overnight in complete MEM at a density of 1xc3x97106 cells/ml at 37xc2x0 C. in 100 ul medium. Test compounds in 50 xcexcl isotonic buffer are added and incubated for 2 hours at 37xc2x0 C. Cell degranulation is triggered by the addition of 25 xcexcl DNP-BSA IgE complex (300 ng/ml DNP-BSA) and incubated an additional 30 min. at 37xc2x0 C. Fifty xcexcl of the cell supernatant from each well is removed and placed in a second 96-well plate which contains 50 xcexcl of substrate solution [90 ml NAGA (hex) buffer (70 ml 0.2M NaPO4, 20 ml 0.4M Citric Acid Monohydrate pH 4.5)+135 ml dH2O, 615 mg p-Nitrophenyl N-acetyl D-glucosaminide]. The reaction is stopped by the addition of 100 xcexcl NAGA stop solution (0.2M Glycine, 0.2M NaCl, 0.2M NaOH) and the plate read at 405 nm on a microtiter plate reader. The compounds of the Examples herein show a desired activity in the assays described.